Project Summary. According to the Centers for Disease Control and Prevention, there were 70,237 drug overdose deaths reported in the United States in 2017, more than 130 per day, with 67.8% involving opioids [1]. While medications are available to treat the disease (e.g., methadone, suboxone, and extended release naltrexone), relapse rates remain alarmingly high [2-4]. Clearly, new approaches are needed. To this end, we recognize that addiction involves not only hijacking of the reward pathway, but also of the need pathway [5]. As such, we posited that heroin seeking and taking should be reduced by peripheral stimulation of the glucagon- like peptide-1 receptor (GLP-1R) ?satiety? pathway. In support, activation of the GLP-1R pathway has been shown to inhibit not only ingestion of palatable sweets, water when thirsty, and salt when sodium deprived, but also responding for alcohol, nicotine, and cocaine in rats and mice [6-12]. Here, we show for the first time that pretreatment with a GLP-1R agonist also reduces heroin taking, seeking, and drug-induced reinstatement in rats. The objective of this application is to test whether treatment with a GLP-1R agonist can reduce relapse in humans with an opioid use disorder (OUD). One advantage of using GLP-1R agonists is that various formulations already are approved for treatment of obesity and type 2 diabetes [13, 14]. UG3 Phase Aim G1 will conduct a randomized, double blind, placebo-controlled pilot study to determine whether once daily treatment with the shorter acting GLP-1R agonist, liraglutide, can safely and effectively reduce craving and brain responses to drug cues among patients in residential treatment for an OUD. UG3 Phase Aim G2 will use well established animal models to test the efficacy and safety of a more risky, longer-acting, but more efficacious, GLP-1R agonist, semaglutide, on heroin seeking and cue/drug/stress-induced reinstatement. Milestones: (1) Demonstrate safety and efficacy liraglutide at approved doses to reduce craving and brain responses to drug cues among patients in residential treatment for OUD who also are receiving counseling only (CO) or counseling+buprenorphine/naltrexone (BUP/NA); (2) Verify that semaglutide is safe and effective in reducing cue/drug/stress-induced heroin seeking in an animal model. If these milestones are met, UH3 Phase Aim H1 will conduct a two-arm, pseudo-randomized, placebo controlled multi-site clinical trial in outpatients with an OUD to test whether treatment with semaglutide vs. placebo will reduce relapse out to 180 days in patients treated with CO and counseling+BUP/NA. UH3 Phase Aim H2 will use animal models to further probe the efficacy and usefulness of semaglutide to prevent initiation of heroin self-administration, to reduce ongoing heroin self-administration, or to serve as a non-opioid ?bridge to care?, for example. If our hypotheses are supported, we will show that treatment with GLP-1R agonists can safely and effectively reduce opioid craving, seeking, and relapse in rats and humans, providing a second indication for full multi-site, Phase III clinical trials, and we will lay the preclinical and clinical groundwork for approval from the FDA.